Hepatocyte growth factor and granulocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy.
BACKGROUND
Myocardial infarction (MI) is a significant cause of heart failure. Current therapies are limited and, therefore, the development of novel revascularization methods is potentially important. We investigated whether hepatocyte growth factor (HGF), expressed by genetically modified mesenchymal stromal cells (MSC), in combination with granulocyte colony-stimulating factor (G-CSF), exhibited a synergistic therapeutic benefit, as measured 8 weeks after MI induction in a rat model.


METHODS
Four weeks after MI, rats were randomly divided into a control group (n=11), HGF group (Adenovirus vector carrying human HGF (Ad-HGF)-transfected MSC transplanted into the infarct zone; n=11), G-CSF group (intraperitoneal injection with G-CSF; n=11), and HGF + G-CSF group (Ad-HGF-transfected MSC transplanted into the infarct zone and intraperitoneal injection with G-CSF; n=11). Four weeks later, hearts were analyzed for endothelial cell density and angiogenesis, ventricular geometry, myocardial function and levels of VCAM-1 and MMP-9 protein.


RESULTS
The HGF + G-CSF group exhibited improved left ventricular systolic and diastolic function and experienced less adverse ventricular remodeling, as manifested by decreased left ventricular dilatation and increased border zone wall thickness. Angiogenesis was significantly enhanced in HGF + G-CSF rats by inducing the proliferation of endothelial cells. Furthermore, HGF induced expression of VCAM-1, and HGF treatment together with G-CSF synergistically stimulated MMP-9 expression in ischemic hearts.


CONCLUSIONS
The combination of G-CSF and HGF exhibited a significant synergistic effect and enhanced myocardial endothelial density, angiogenesis, geometric preservation and heart function in an ischemic cardiomyopathy model.
Guo
Ying-Hua
YH
Department of Respiration, Chinese PLA General Hospital, Beijing, PR China.
He
Jian-Guo
JG
Wu
Jun-Lou
JL
Yang
Long
L
Zhang
Dong-Sheng
DS
Tan
Xiao-Yan
XY
Qi
Rui-Dong
RD
D000818:Animals; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007267:Injections; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D009203:Myocardial Infarction / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D020127:Recovery of Function; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D014162:Transfection; D019076:Transgenes / Q000235:genetics / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D017228:Hepatocyte Growth Factor; D020780:Matrix Metalloproteinase 9